Polymer-drug conjugates for novel molecular targets

Nanomedicine

Volumn 5, Issue 6, 2010, Pages 915-935

  Sanchis, Joaquin ^a   Canal, Fabiana ^a   Lucas, Rut ^a   Vicent, Mara J ^a  

^a Polymer Therapeutics Laboratory   (Spain)

Author keywords

cancer; nanomedicine; novel molecular targets; polymer therapeutics; polymerdrug conjugate; targeted drug delivery; tissue repair

Indexed keywords

AD 70; ANTIFUNGAL AGENT; ANTINEOPLASTIC AGENT; ANTIPROTOZOAL AGENT; ANTIVIRUS AGENT; AP5280; CAMPTOTHECIN; CARBOXYMETHYL DEXTRAN EXATECAN; CT 2106; CYCLODEXTRIN; CYCLODEXTRIN CAMPTOTHECIN; DE 310; DOXORUBICIN; EXATECAN; FLEXIMER CAMPTOTHECIN; HEAT SHOCK PROTEIN 90; HPMA COPOLYMER CAMPTOTHECIN; HPMA COPOLYMER DACH PLATINATE; HPMA COPOLYMER DOXORUBICIN; HPMA COPOLYMER DOXORUBICIN GALACTOSAMINE; HPMA COPOLYMER MALONATO PLATINATE; HPMA COPOLYMER PACLITAXEL; IRINOTECAN; IT 101; MACROGOL; MACROGOL CAMPTOTHECIN; MACROGOL DOCETAXEL; MACROGOL IRINOTECAN; MAG CPT; NKTR 102; NKTR 105; OPAXIO; OXIDIZED DEXTRAN DOXORUBICIN; PEGAMOTECAN; PHOSPHOTRANSFERASE; PK 1; PK 2; PNU 166945; POLYGLUTAMIC ACID; POLYGLUTAMIC ACID CAMPTOTHECIN; POLYGLUTAMIC ACID PACLITAXEL; POLYMER; PROLINDAC; UNCLASSIFIED DRUG; UNINDEXED DRUG; XMT 1001;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER THERAPY; CLINICAL EFFECTIVENESS; DIABETES MELLITUS; DRUG CONJUGATION; DRUG DELIVERY SYSTEM; DRUG TARGETING; ENZYME INHIBITION; GASTROINTESTINAL DISEASE; HUMAN; HYPERTENSION; ISCHEMIA; MOLECULAR THERAPY; NANOMEDICINE; OSTEOPOROSIS; PRIORITY JOURNAL; REGENERATIVE MEDICINE; REPERFUSION INJURY; REVIEW; SEPSIS; TISSUE REPAIR; VIRUS INFECTION; WOUND HEALING;

PHARMACEUTICAL PREPARATIONS; POLYMERS;

EID: 77956073874     PISSN: 17435889     EISSN: None     Source Type: Journal    
DOI: 10.2217/nnm.10.71     Document Type: Review

References (149)

1. Duncan R: The dawning era of polymer therapeutics. Nat. Rev. DrugDiscov. 2(5), 347-360 (2003).
2. Haag R, Kratz F: Polymer therapeutics: Concepts and applications. Angew. Chem. Int. Ed. 45(8), 1198-1215 (2006).
3. Duncan R: Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer 6(9), 688-701 (2006).
4. Li C, Wallace S: Polymer-drug conjugates: recent development in clinical oncology. Adv. Drug Deliv. Rev. 60(8), 886-898 (2008).
5. Vicent MJ, Duncan R: Polymer therapeutics: clinical applications and challenges for development. Adv. Drug Deliv. Rev. 61(13), 1117-1232 (2009).
6. Ringsdorf H: Structure and properties of pharmacologically active polymers. J. Polym. Sci. C-Polym. Symp. 51, 135-153 (1975).
7. Meerum Terwogt JM, Ten Bokkel Huinink WW, Schellens JH et al.: Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel. Anticancer Drugs 12(4), 315-323 (2001).
8. Vasey PA, Kaye SB, Morrison R et al.: Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl) methacrylamide copolymer doxorubicin]: first member of a new class of chemotherapeutic agents -drug-polymer conjugates. Clin. Cancer Res. 5(1), 83-94 (1999).
9. Yurkovetskiy AV, Fram RJ: XMT-1001, a novel polymeric camptothecin pro-drug in clinical development for patients with advanced cancer. Adv. Drug Deliv. Rev. 61(13), 1193-1202 (2009).
10. Brocchini S, Duncan R: Polymer-drug conjugates: drug release from pendent linkers. In: Encyclopaedia of controlled release. Mathiowitz E (Ed.). Wiley, NY, USA 786-816 (1999).
11. Duncan R, Cable HC, Lloyd JB, Rejmanova P, Kopecek J: Polymers containing enzymatically degradable bonds .7. Design of oligopeptide side-chains in poly[N-(2-hydroxypropyl)methacrylamide] co-polymers to promote efficient degradation by lysosomal-enzymes. Makromol. Chem. Macromol. Chem. Phys. 184(10), 1997-2008 (1983).
12. Allen TM: Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer 2(10), 750-763 (2002).
13. Brumlik MJ, Daniel BJ, Waehler R, Curiel DT, Giles FJ, Curiel TJ: Trends in immunoconjugate and ligand-receptor based targeting development for cancer therapy. Expert Opin. Drug Deliv. 5(1), 87-103 (2008).
14. Seymour LW, Ferry DR, Anderson D et al.: Hepatic drug targeting: Phase I evaluation of polymer-bound doxorubicin. J. Clin. Oncol. 20(6), 1668-1676 (2002).
15. Matsumura Y, Maeda H: A new concept for macromolecular therapeutics in cancer-chemotherapy -mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res. 46(12), 6387-6392 (1986).
16. Iyer AK, Khaled G, Fang J, Maeda H: Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov. Today 11(17-18), 812-818 (2006).
17. Vicent MJ, Duncan R: Polymer conjugates: nanosized medicines for treating cancer. Trends Biotechnol. 24(1), 39-47 (2006).
18. Vicent MJ, Ringsdorf H, Duncan R: Polymer therapeutics: clinical applications and challenges for development. Adv. Drug Deliv. Rev. 61(13), 1117-1120 (2009).
19. Chipman SD, Oldham FB, Pezzoni G, Singer JW: Biological and clinical characterization of paclitaxel poliglumex (PPX, CT-2103), a macromolecular polymer-drug conjugate. Int. J. Nanomed. 1(4), 375-383 (2006).
20. Seymour LW, Ferry DR, Kerr DJ et al.: Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer. Int. J. Oncol. 34(6), 1629-1636 (2009).
21. Danhauserriedl S, Hausmann E, Schick HD et al.: Phase-I clinical and pharmacokinetic trial of dextran conjugated doxorubicin (AD-70, DOX-OXD). Invest. New Drugs 11(2-3), 187-195 (1993).
22. Springett GM, Takimoto C, McNamara M et al.: Phase I study of CT-2106 (polyglutamate camptothecin) in patients with advanced malignancies. J. Clin. Oncol. 22(14), 3127 (2004).
23. Schluep T, Hwang J, Cheng JJ et al.: Preclinical efficacy of the camptothecin-polymer conjugate IT-101 in multiple cancer models. Clin. Cancer Res. 12(5), 1606-1614 (2006).
24. Bissett D, Cassidy J, de Bono JS et al.: Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT). Brit. J. Cancer 91(1), 50-55 (2004).
25. Soepenberg O, de Jonge MJA, Sparreboom A et al.: Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors. Clin. Cancer Res. 11(2), 703-711 (2005).
26. Davis ME: Design and development of IT-101, a cyclodextrin-containing polymer conjugate of camptothecin. Adv. Drug Deliv. Rev. 61(13), 1189-1192 (2009).
27. Li C, Yu DF, Newman RA et al.: Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid) paclitaxel conjugate. Cancer Res. 58(11), 2404-2409 (1998).
28. Singer JW, Shaffer S, Baker B et al.: Paclitaxel poliglumex (XYOTAX; CT-2103): an intracellularly targeted taxane. Anticancer Drugs 16(3), 243-254 (2005).
29. Shaffer SA, Baker Lee C, Kumar A, Singer JW: Proteolysis of XYOTAX by lysosomal cathepsin B; metabolic profiling in tumor cells using LC-MS. Eur. J. Cancer 38, 428 (2002).
30. Rademaker-Lakhai JM, Terret C, Howell SB et al.: A Phase I and pharmacological study of the platinum polymer AP5280 given as an intravenous infusion once every 3 weeks in patients with solid tumors. Clin. Cancer Res. 10(10), 3386-3395 (2004).
31. Nowotnik DP, Cvitkovic E: ProLindac™ (AP5346): a review of the development of an HPMA DACH platinum polymer therapeutic. Adv. Drug Deliv. Rev. 61(13), 1214-1219 (2009).
32. Greco F, Vicent MJ: Polymer-drug conjugates: current status and future trends. Frontiers Biosci. 13, 2744-2756 (2008).
33. Vicent MJ, Dieudonne L, Carbajo RJ, Pineda-Lucena A: Polymer conjugates as therapeutics: future trends, challenges and opportunities. Expert Opin. Drug Deliv. 5(5), 593-614 (2008).
34. Gaspar R, Duncan R: Polymeric carriers: preclinical safety and the regulatory implications for design and development of polymer therapeutics. Adv. Drug Deliv. Rev. 61(13), 1220-1232 (2009).
35. Lammers T: Improving the efficacy of combined modality anticancer therapy using HPMA copolymer-based nanomedicine formulations. Adv. Drug Deliv. Rev. 62(2), 203-230 (2010).
36. Greco F, Vicent MJ: Combination therapy: Opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines. Adv. Drug Deliv. Rev. 61(13), 1203-1213 (2009).
37. Satchi-Fainaro R, Duncan R, Barnes CM: Polymer therapeutics for cancer: current status and future challenges. Polymer Therapeutics II193, 1-65 (2006).
38. Khandare J, Minko T: Polymer-drug conjugates: progress in polymeric prodrugs. Progr. Polym. Sci. 31(4), 359-397 (2006).
39. Lammers T, Ulbrich K: HPMA copolymers: 30 years of advances. Adv. Drug Deliv. Rev. 62(2), 119-121 (2009).
40. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100(1), 57-70 (2000).
41. Gerber HP, McMurtrey A, Kowalski J et al.: Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase Akt signal transduction pathway -requirement for Flk-1/KDR activation. J. Biol. Chem. 273(46), 30336-30343 (1998).
42. Arcaro A, Wymann MP: Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor -the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J. 296, 297-301 (1993).
43. Vlahos CJ, Matter WF, Hui KY, Brown RF: A specific inhibitor of phosphatidylnositol 3-kinase, 2-(4-morpholinyl) -8-phenyl-4h-1-benzopyran-4-one (Ly294002). J. Biol. Chem. 269(7), 5241-5248 (1994).
44. Varticovski L, Lu ZR, Mitchell K, de Aos I, Kopecek J: Water-soluble HPMA copolymer-wortmannin conjugate retains phosphoinositide 3-kinase inhibitory activity in vitro and in vivo. J. Control. Rel. 74(1-3), 275-281 (2001).
45. Bae Y, Diezi TA, Zhao A, Kwon GS: Mixed polymeric micelles for combination cancer chemotherapy through the concurrent delivery of multiple chemotherapeutic agents. J. Control. Rel. 122, 324-330 (2007).
46. Takabe K, Paugh SW, Milstien S, Spiegel S: 'Inside-out' signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol. Rev. 60(2), 181-195 (2008).
47. Avery K, Avery S, Shepherd J, Heath PR, Moore H: Sphingosine-1-phosphate mediates transcriptional regulation of key targets associated with survival, proliferation, and pluripotency in human embryonic stem cells. Stem Cells Dev. 17(6), 1195-1205 (2008).
48. Huwiler A, Pfeischifter J: New players on the center stage: sphingosine 1-phosphate and its receptors as drug targets. Biochem. Pharmacol. 75(10), 1893-1900 (2008).
49. Ghosh SC, Auzenne E, Khodadadian M, Farquhar D, Klostergaard J: N,N-dimethylsphingosine conjugates of poly-L-glutamic acid: synthesis, characterization, and initial biological evaluation. Bioorg. Med. Chem. Lett. 19(3), 1012-1017 (2009).
50. Richter K, Buchner J: HSP90: chaperoning signal transduction. J. Cell. Physiol. 188(3), 281-290 (2001).
51. Blagosklonny MV: HSP-90-associated oncoproteins: multiple targets of geldanamycin and its analogs. Leukemia 16(4), 455-462 (2002).
52. Borgman MP, Ray A, Kolhatkar RB, Sausville EA, Burger AM, Ghandehari H: Targetable HPMA copolymer-aminohexylgeldanamycin conjugates for prostate cancer therapy. Pharm. Res. 26(6), 1407-1418 (2009).
53. Bae Y, Buresh RA, Williamson TP, Chen TH, Furgeson DY: Intelligent biosynthetic nanobiomaterials for hyperthermic combination chemotherapy and thermal drug targeting of HSP90 inhibitor geldanamycin. J. Control. Rel. 122(1), 16-23 (2007).
54. Alam JJ: Apoptosis: target for novel drugs. Trends Biotechnol. 21(11), 479-483 (2003).
55. Reed JC: Apoptosis-based therapies. Nat. Rev. Drug Discov. 1(2), 111-121 (2002).
56. Green DR: Apoptotic pathways: ten minutes to dead. Cell 121(5), 671-674 (2005).
57. Vicent MJ: Polymer-drug conjugates as modulators of cellular apoptosis. AAPS J. 9(2), E200-207 (2007).
58. Sharma RA, Gescher AJ, Steward WP: Curcumin: the story so far. Eur. J. Cancer 41(13), 1955-1968 (2005).
59. Li J, Wang Y, Yang C et al.: PEGylated curcumin conjugate inhibits pancreatic cancer cell growth through inactivation of Jab1. Mol. Pharmacol. 76(1), 81-90 (2009).
60. Juin P, Geneste O, Raimbaud E, Hickman JA: Shooting at survivors: Bcl-2 family members as drug targets for cancer. Biochim. Biophys. Acta 1644(2-3), 251-260 (2004).
61. Oman M, Liu JH, Chen J et al.: Using N-(2-hydroxypropyl) methacrylamide copolymer drug bioconjugate as a novel approach to deliver a Bcl-2-targeting compound HA14-1 in vivo. Gen. Ther. Mol. Biol. 10A, 113-122 (2006).
62. Greco F, Vicent MJ, Penning NA, Nicholson RI, Duncan R: HPMA copolymer-aminoglutethimide conjugates inhibit aromatase in MCF-7 cell lines. J. Drug Target. 13(8-9), 459-470 (2005).
63. Vicent MJ, Greco F, Nicholson RI, Paul A, Griffiths PC, Duncan R: Polymer therapeutics designed for a combination therapy of hormone-dependent cancer. Angew. Chem. Int. Ed. 44(26), 4061-4066 (2005).
64. Greco F, Vicent MJ, Gee S et al.: Investigating the mechanism of enhanced cytotoxicity of HPMA copolymer-Dox-AGM in breast cancer cells. J. Control. Rel. 117(1), 28-39 (2007).
65. Lammers T, Subr V, Ulbrich K et al.: Simultaneous delivery of doxorubicin and gemcitabine to tumors in vivo using prototypic polymeric drug carriers. Biomaterials 30(20), 3466-3475 (2009).
66. Santucci L, Mencarelli A, Renga B et al.: Nitric oxide modulates proapoptotic and antiapoptotic properties of chemotherapy agents: the case of NO-PEGylated epirubicin. FASEBJ. 20(2), 765-776 (2006).
67. Santucci L, Mencarelli A, Renga B et al.: Cardiac safety and antiturnoral activity of a new nitric oxide derivative of PEGylated epirubicin in mice. Anti-Cancer Drugs 18(9), 1081-1091 (2007).
68. Folkman J: Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182-1186 (1971).
69. Segal E, Satchi-Fainaro R: Design and development of polymer conjugates as anti-angiogenic agents. Adv. Drug Deliv. Rev. 61(13), 1159-1176 (2009).
70. Kragh M, Spang-Thomsen M, Kristjansen PE: Time until initiation of tumor growth is an effective measure of the anti-angiogenic effect of TNP-470 on human glioblastoma in nude mice. Oncol. Rep. 6(4), 759-762 (1999).
71. Satchi-Fainaro R, Puder M, Davies JW et al.: Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat. Med. 10(3), 255-261 (2004).
72. Satchi-Fainaro R, Mamluk R, Wang L et al.: Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell 7(3), 251-261 (2005).
73. Chesler L, Goldenberg DD, Seales IT et al.: Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma. Cancer Res. 67, 9435-9442 (2007).
74. Benny O, Fainaru O, Adini A et al.: An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nat. Biotechnol. 26(7), 799-807 (2008).
75. Segal E, Pan H, Ofek P et al.: Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics. PLoS One 4(4), e5233 (2009).
76. Browder T, Butterfield CE, Kraling BM et al.: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer. Res. 60, 1878-1886 (2000).
77. Miller K, Erez R, Segal E, Shabat D, Satchi-Fainaro R: Targeting bone metastases with a bispecific anticancer and antiangiogenic polymer-alendronate- taxane conjugate. Angew. Chem. Int. Ed. 48(16), 2949-2954 (2009).
78. Zhu G, Cao X, Chang JY, Milas L, Wallace S, Li C: Polymeric retinoid prodrug PG-4HPR enhances the radiation response of lung cancer. Oncol. Rep. 18(3), 645-651 (2007)
79. Cuchelkar V, Kopeckova P, Kopecek J: Synthesis and biological evaluation of disulfide-linked HPMA copolymer-mesochlorin e6 conjugates. Macromol. Biosci. 8(5), 375-383 (2008).
80. Lammers T, Peschke P, Kuhnlein R et al.: Effect of radiotherapy and hyperthermia on the tumor accumulation of HPMA copolymer-based drug delivery systems. J. Control. Rel. 117(3), 333-341 (2007).
81. Lammers T, Subr V, Peschke P et al.: Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy. Br. J. Cancer 99 (6), 900-910 (2008).
82. Bettio F, Canevari M, Marzano C et al.: Synthesis and biological in vitro evaluation of novel PEG-psoralen conjugates. Biomacromol. 7(12), 3534-3541 (2006).
83. Tsujihara K, Hongu M, Saito K et al.: Na+-glucose cotransporter inhibitors as antidiabetics. 1. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives based on a new concept. Chem. Pharm. Bull. 44(6), 1174-1180 (1996).
84. Ikumi Y, Kida T, Sakuma S, Yamashita S, Akashi M: Polymer-phloridzin conjugates as an anti-diabetic drug that inhibits glucose absorption through the Na+/glucose cotransporter (SGLT1) in the small intestine. J. Control. Rel. 125(1), 42-49 (2008).
85. Sakuma S, Sagawa T, Masaoka Y et al.: Stabilization of enzyme-susceptible glucoside bonds of phloridzin through conjugation with poly(g-glutamic acid). J. Control. Rel. 133(2), 125-131 (2009).
86. Miyamoto Y, Akaike T, Yoshida M, Goto S, Horie H, Maeda H: Potentiation of nitric oxide-mediated vasorelaxation by xanthine oxidase inhibitors. Proc. Soc. Exp. Biol. Med. 211(4), 366-373 (1996).
87. Fang J, Iyer AK, Seki T, Nakamura H, Greish K, Maeda H: SMA-copolymer conjugate of AHPP: a polymeric inhibitor of xanthine oxidase with potential antihypertensive effect. J. Control. Rel. 135(3), 211-217 (2009).
88. Flexner C: HIV-protease inhibitors. N. Engl. J. Med. 338(18), 1281-1292 (1998).
89. Gunaseelan S, Debrah O, Wan L et al.: Synthesis of poly(ethylene glycol)-based saquinavir prodrug conjugates and assessment of release and anti-HIV-1 bioactivity using a novel protease inhibition assay. Bioconjug. Chem. 15(6), 1322-1333 (2004).
90. Wan L, Zhang X, Gunaseelan S et al.: Novel multi-component nanopharmaceuticals derived from poly(ethylene) glycol, retro-inverso-Tat nonapeptide and saquinavir demonstrate combined anti-HIV effects. AIDS Res. Ther. 3, 12 (2006).
91. Gao Y, Katsuraya K, Kaneko Y, Mimura T, Nakashima H, Uryu T: Synthesis of Azidothymidine-bound sulfated alkyl oligosaccharides and their inhibitory effects on AIDS virus infection in vitro. Polym. J. 30, 243-248 (1998).
92. Vlieghe P, Clerc T, Pannecouque C et al.: Synthesis of new covalently bound k-carrageenan-AZT conjugates. J. Med. Chem. 45, 1275-1283 (2002).
93. Wannachaiyasit S, Chanvorachote P, Nimmannit U: A novel anti-HIV dextrin-zidovudine conjugate improving the pharmacokinetics of zidovudine in rats. AAPS Pharm. Sci. Tech. 9(3), 840-850 (2008).
94. Giammona G, Cavallaro G, Pitarresi G: Studies of macromolecular prodrugs of zidovudine. Adv. Drug Deliv. Rev. 39, 153-164 (1999).
95. Chimalakonda KC, Agarwal HK, Kumar A, Parang K, Mehvar R: Synthesis, analysis, in vitro characterization, and in vivo disposition of a lamivudine-dextran conjugate for selective antiviral delivery to the liver. Bioconjug. Chem. 18(6), 2097-2108 (2007).
96. Heidemann HT, Gerkens JF, Jackson EK, Branch RA: Effect of aminophylline on renal vasoconstriction produced by amphotericin B in the rat. Naunyn Schmi. Arch. Pharmacol. 324(2), 148-152 (1983).
97. Cereghetti DM, Carreira EM: Amphotericin B: 50 years of chemistry and biochemistry. Synthesis-Stuttgart (6), 914-942 (2006).
98. Trejo WH, Bennett RE: Streptomyces nodosus sp. n., the amphotericin-producing organism. J. Bacteriol. 85, 436-439 (1963).
99. Sedlak M, Buchta V, Kubicova L, Simunek P, Holcapek M, Kasparova P: Synthesis and characterisation of a new amphotericin B-methoxypoly(ethylene glycol) conjugate. Bioorg. Med. Chem. Lett. 11(21), 2833-2835 (2001).
100. Sedlak M, Pravda M, Staud F, Kubicova L, Tycova K, Ventura K: Synthesis of pH-sensitive amphotericin B-poly(ethylene glycol) conjugates and study of their controlled release in vitro. Bioorg. Med. Chem. 15(12), 4069-4076 (2007).
101. Sedlak M, Drabina P, Bilkova E, Simunek P, Buchta V: New targeting system for antimycotic drugs: p-glucosidase sensitive amphotericin B-star poly(ethylene glycol) conjugate. Bioorg. Med. Chem. Lett. 18(9), 2952-2956 (2008).
102. Chappuis F, Sundar S, Hailu A et al.: Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat. Rev. Microbiol. 5(11), 873-882 (2007).
103. Mueller Y, Nguimfack A, Cavailler P et al.: Safety and effectiveness of amphotericin B deoxycholate for the treatment of visceral leishmaniasis in Uganda. Ann. Trop. Med. Parasitol. 102(1), 11-19 (2008).
104. Golenser J, Frankerburg S, Erhenfreund T, Domb AJ: Efficacious treatment of experimental leishmaniasis with amphotericin B-arabinogalactan water-soluble derivatives Antimicrob. Agent Chemother. 43(9), 2209-2214 (1999).
105. Nicoletti S, Seifert K, Gilbert IH: N-(2-hydroxypropyl)methacrylamide- amphotericin B (HPMA-AmB) copolymer conjugates as antileishmanial agents. Int. J. Antimicrob. Agents 33(5), 441-448 (2009).
106. Chaudhuri G, Mukhopadhyay A, Basu SK: Selective delivery of drugs to macrophages through a highly specific receptor. An efficient chemotherapeutic approach against leishmaniasis. Biochem. Pharmacol. 38, 2995-3002 (1989).
107. Nan A, Nanayakkara NP, Walker LA, Yardley V, Croft SL, Ghandehari H: N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers for targeted delivery of 8-aminoquinoline antileishmanial drugs. J. Control. Rel. 94, 115-127 (2001).
108. Nan A, Croft SL, Yardley V, Ghandehari H: Targetable water-soluble polymer-drug conjugates for the treatment of visceral leishmaniasis. J. Control. Rel. 94, 115-127 (2004).
109. Minino AM, Heron MP, Murphy SL, Kochanek KD: Deaths: final data for 2004. Natl Vital. Stat. Rep. 55(19), 1-119 (2007).
110. Heine H, Rietschel ET, Ulmer AJ: The biology of endotoxin. Mol. Biotechnol. 19(3), 279-296 (2001).
111. Vincent JL: Drotrecogin a (activated): the treatment for severe sepsis? Expert Opin. Biol. Ther. 7(11), 1763-1777 (2007).
112. Cruz DN, Perazella MA, Bellomo R et al.: Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review. Crit. Care 11(2), R47 (2007).
113. Shoji H: Extracorporeal endotoxin removal for the treatment of sepsis: endotoxin adsorption cartridge (Toraymyxin). Ther. Apher. Dial. 7(1), 108-114 (2003).
114. Vicent MJ, Cascales L, Carbajo RJ, Cortes N, Messeguer A, Perez-Paya E: Nanoconjugates as intracorporeal neutralizers of bacterial endotoxins. J. Control. Rel. 142, 277-285 (2010).
115. Pasut G, Veronese FM: PEG conjugates in clinical development or use as anticancer agents: an overview. Adv. Drug Deliv. Rev. 61(13), 1176-1188 (2009).
116. Rodriguez M, Antunez JA, Taboada C, Seijo B, Torres D: Colon-specific delivery of budesonide from microencapsulated cellulosic cores: evaluation of the efficacy against colonic inflammation in rats. J. Pharm. Pharmacol. 53(9), 1207-1215 (2001).
117. Varshosaz J, Emami J, Tavakoli N et al.: Synthesis and evaluation of dextran-budesonide conjugates as colon specific prodrugs for treatment of ulcerative colitis. Int. J. Pharm. 365(1-2), 69-76 (2009).
118. Keely S, Ryan SM, Haddleton DM et al.: Dexamethasone-pDMAEMA polymeric conjugates reduce inflammatory biomarkers in human intestinal epithelial monolayers. J. Control. Rel. 135(1), 35-43 (2009).
119. Henson PM: Dampening inflammation. Nat. Immunol. 6, 1179-1181 (2005).
120. Liu X-M, Miller SC, Wang D: Beyond oncology-Application of HPMA copolymers in non-cancerous diseases. Adv. Drug Deliv. Rev. 62, 258-271 (2010).
121. Wang D, Miller SC, Liu XM, Anderson B, Wang XS, Goldring SR: Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis. Arthritis Res. Ther. 9(1), R2 (2007).
122. Hwang J, Rodgers K, Oliver JC, Schluep T: a-methylprednisolone conjugated cyclodextrin polymer-based nanoparticles for rheumatoid arthritis therapy. Int. J. Nanomed. 3(3), 359-371 (2008).
123. Kurtoglu YE, Navath RS, Wang B, Kannan S, Romero R, Kannan RM: Poly(amidoamine) dendrimer-drug conjugates with disulfide linkages for intracellular drug delivery. Biomaterials 30(11), 2112-2121 (2009).
124. Hardwicke J, Ferguson EL, Moseley R, Stephens P, Thomas DW, Duncan R: Dextrin-rhEGF conjugates as bioresponsive nanomedicines for wound repair. J. Control. Rel. 130(3), 275-283 (2008).
125. Vicent MJ, Perez-Paya E: Poly-L-glutamic acid (PGA) aided inhibitors of apoptotic protease activating factor 1 (Apaf-1): an antiapoptotic polymeric nanomedicine. J. Med. Chem. 49(13), 3763-3765 (2006).
126. Shaunak S, Thomas S, Gianasi E et al.: Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation. Nat. Biotechnol. 22(8), 977-984 (2004).
127. Fisher M: The ischemic penumbra: identification, evolution and treatment conecpts. Cerebrovasc. Dis. 17(Suppl. 1), 1-6 (2004).
128. Bertuglia S, Giusti A: Microvascular oxygenation, oxidative stress, NO suppression and superoxide dismutase during postischemic reperfusion. Am. J. Physiol. Heart Circ. Physiol. 285(3), H1064-H1071 (2003).
129. Mondragon L, Orzaez M, Sanclimens G et al.: Modulation of cellular apoptosis with apoptotic protease-activating factor 1 (Apaf-1) inhibitors. J. Med. Chem. 51(3), 521-529 (2008).
130. Vicent MJ, Mondragon L, Orzaez M et al.: Polymer-drug conjugates as inhibitors of cellular apoptosis. AAPS J. 35, 230 (2008).
131. Goicoechea I, Peri L, Vicent MJ et al.: Evaluation of apoptosis inhibition using Apaf-1 inhibitors (peptoid 1) in an ischaemia-reperfusion Wistar rat model. Eur. Urol. 8(Suppl. 4), 144 (2009).
132. Koh KK: Effects of hormone replacement therapy on coagulation and fibrinolysis in postmenopausal women. Int. J. Hematol. 76(Suppl. 2), 44-46 (2002).
133. Di Bitondo R, Hall AJ, Peake IR, Iacoviello L, Winship PR: Oestrogenic repression of human coagulation factor VII expression mediated through an oestrogen response element sequence motif in the promoter region. Hum. Mol. Genet. 11(7), 723-731 (2002).
134. Rodriguez-Hernandez A, Rubio-Gayosso I, Ramirez I et al.: Intraluminal-restricted 17 p-estradiol exerts the same myocardial protection against ischemia/reperfusion injury in vivo as free 17 p-estradiol. Steroids 73(5), 528-538 (2008).
135. Bertuglia S, Veronese FM, Pasut G: Polyethylene glycol and a novel developed polyethylene glycol-nitric oxide normalize arteriolar response and oxidative stress in ischemia-reperfusion. Am. J. Physiol. Heart Circ. Physiol. 291(4), H1536-H1544 (2006).
136. Wang D, Miller SC, Kopeckova P, Kopecek J: Bone-targeting macromolecular therapeutics. Adv. Drug Deliv. Rev. 57(7), 1049-1076 (2005).
137. Lindsay R: Hormones and bone health in postmenopausal women. Endocrine 24(3), 223-230 (2004).
138. Pan H, Liu J, Dong Y et al.: Release of prostaglandin E(1) from N-(2-hydroxypropyl) methacrylamide copolymer conjugates by bone cells. Macromol. Biosci. 8(7), 599-605 (2008).
139. Pan H, Sima M, Kopeckova P et al.: Biodistribution and pharmacokinetic studies of bone-targeting N-(2-hydroxypropyl) methacrylamide copolymer-alendronate conjugates. Mol. Pharm. 5(4), 548-558 (2008).
140. Wang D, Miller S, Sima M, Kopeckova P, Kopecek J: Synthesis and evaluation of water-soluble polymeric bone-targeted drug delivery systems. Bioconjug. Chem. 14, 853-859 (2003).
141. Greco F, Vicent MJ: Polymer conjugates based combinations for improved treatment of cancer. Adv. Drug Deliv. Rev. 61(13), 1203-1213 (2009).
142. Eskens F, Verweij J: The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors. A review. Eur. J. Cancer 42(18), 3127-3139 (2006).
143. Rowinsky EK, Rizzo J, Ochoa L et al.: A Phase I and pharmacokinetic study of PEGylated camptothecin as a 1-hour infusion every 3 weeks in patients with advanced solid malignancies. J. Clin. Oncol. 21(1), 148-157 (2003).
144. Cerulean Nanopharmaceuticals www.ceruleanrx.com/ scienceNanopharmaceuticals.html
145. Nektar: NXTR-102 www.nektar.com/product-pipeline/ oncology-nktr-102.html
146. CTI. Clinical development: OPAXIO™ www.celltherapeutics.com/opaxio
147. Nektar: NXTR-105 www.nektar.com/product-pipeline/ oncology-nktr-105.html
148. SynDevRx™, Inc. Synergistic drug development www.syndevrx.com
149. Nectar: Oral NKTR-118 and Oral NKTR-119 www.nektar.com/product-pipeline/ cns- pain-oral-nktr-118and119.html